Role Of Stereoelectronic Effects Research Articles

Exploiting the role of stereoelectronic effects to design the antagonists of the human complement C3a receptor

Stereoelectronic effects are crucial in governing the conformational behaviour of small molecules bearing heterocyclic rings adjacent to amides.

Towards the Design of Optically Active Thiophene S-Oxides using Quantum Chemistry.

The importance of axially chiral biaryls has risen steeply in the recent decades. This structural motif proved to be successful in catalytic asymmetric synthesis and the configuration of the biaryl axis is decisive for the biological activity. A new approach for the atroposelective synthesis of biaryls would be through a cycloaddition between an enantiopure phenyl-substituted thiophene S-oxide and an alkyne. Importantly, the chiral center of the thiophene S-oxide needs to be stable enough to avoid pyramidal inversion during the cycloaddition. Considering that the racemization of thiophene monoxides has been scarcely investigated so far, we perform a thorough quantum chemical study on the inversion barriers of a large number of chiral thiophene S-oxide derivatives. Our main goal is to identify substitution patterns leading to stable atropisomers at room temperature. Appealingly, the role of stereoelectronic effects and the position of the substituents as well as the importance of aromaticity on the pyramidal inversion barrier are elucidated for the first time.

Hydrogen Abstraction from Cyclic Amines by the Cumyloxyl and Benzyloxyl Radicals. The Role of Stereoelectronic Effects and of Substrate/Radical Hydrogen Bonding

A kinetic study on the hydrogen abstraction reactions from cyclic amines and diamines (pyrrolidines, piperidines, morpholines, and piperazines) by the cumyloxyl (CumO(•)) and benzyloxyl (BnO(•)) radicals was carried out. The reactions with CumO(•) were described in all cases as direct hydrogen abstractions. The differences in the hydrogen abstraction rate constant (k(H)) were explained in terms of the different number of abstractable hydrogen atoms, the operation of stereoelectronic effects, and, with the morpholines, on the basis of polar effects. Significantly higher k(H) values were measured for the reactions of the amines with BnO(•). This behavior was explained on the basis of a mechanism that proceeds through the rate-determining formation of a hydrogen bonded pre-reaction complex between the radical α-C-H and the nitrogen lone pair followed by hydrogen abstraction within the complex. A decrease in k(H) was observed going from secondary to tertiary amines and, with tertiary amines, on increasing steric hindrance at nitrogen, pointing toward the important role of steric and electronic effects on pre-reaction complex formation. These results expand previous findings contributing to a detailed mechanistic description of the reactions of alkoxyl radicals with amines, showing that structural effects in both the substrate and the radical can play a dramatic role and providing new information on the role of substrate/radical interactions on these processes.

Stereoelectronic effects on the transition barrier of polyproline conformational interconversion

There has been growing interest in polyproline type II (PPII) helices since PPII helices have been found in folded and unfolded proteins and involved in a variety of biological activities. Polyproline can also form type I helices (PPI) which are very different from PPII conformation and only exist in certain organic solvents. Recent studies have shown that stereoelectronic effects play a critical role in stabilizing a PPI or PPII helix. Here, we have synthesized a series of host-guest peptides with an electron-withdrawing substituent at the 4R or 4S position of proline and used a kinetic approach to further explore stereoelectronic effects on the transition barrier of the interconversion between PPI and PPII conformations. Time-dependent circular dichroism measurements revealed that the rates of PPII --> PPI conversion were reduced upon incorporating the hydroxyl-, fluoro-, and methoxy-groups at the 4R position while the rates would be increased if these substituents were at the 4S position. We quantified the changes in transition free energy by comparing their rate constants. (4R,2S)-4-Fluoroproline and (4S,2S)-4-fluoroproline have the largest effect on the transition energy barrier for PPII --> PPI conversion. Our results provide important insights into the role of stereoelectronic effects on the PPII --> PPI transition state barrier, which has not been reported in past thermodynamic studies.

Analysis of the Decarboxylation Step in Mammalian Histidine Decarboxylase: A COMPUTATIONAL STUDY

We report a hybrid quantum mechanics/molecular mechanics theoretical study on the reaction mechanism of mammalian histidine decarboxylase that allows us to obtain valuable insights on the structure of the cofactor-substrate adduct (external aldimine) in the active site of rat histidine decarboxylase. By means of molecular dynamics simulations, we traced the potential of mean force corresponding to the decarboxylation reaction of the adduct both in the active site of the enzyme and in aqueous solution. By comparing this process in both media, we have identified the key electrostatic interactions that explain the lowering of the free energy barrier in the enzyme. Our analysis also offers a validation of Dunathan's hypothesis (Dunathan, H. (1966) Proc. Natl. Acad. Sci. U. S. A. 55, 712-716) regarding the role of stereoelectronic effects in the enzymatic decarboxylation process.

On the role of stereo-electronic effects in tuning the selectivity and rate of DNA alkylation by duocarmycins

The role of local geometric and stereo-electronic effects in tuning the alkylation of DNA by duocarmycins has been analyzed by an integrated computational tool rooted in the density functional theory and the polarizable continuum model. Our study points out that together with steric accessibility, different electronic delocalisations also contribute to determine the higher reactivity of adenine with respect to guanine. Also the effect of the methyl ester group on the alkylating agent has an electronic origin. Furthermore, deviations from the planarity in the drug structure (conformational catalysis) could be less important than currently accepted since, according to our computations, compounds with strongly different reactivity have nearly constant and very similar out of plane distortions before and after the reaction. Model computations suggest, instead, that specific non covalent interactions could discriminate between different drugs selectively reducing some activation energies with respect to the corresponding processes in solution.

The role of stereoelectronic effects on the side-chain fragmentation of alkylaromatic radical cations. The reactivity of 5-methoxy-2,2-dimethylindan-1-ol radical cation

A kinetic and products study of the reaction of 2,2-dimethyl-5-methoxyindan-1-ol ( 1 ) radical cation, in acidic aqueous solution (pH≤4) has been carried out. 1 + undergoes C–H deprotonation as the exclusive reaction with k=4.6×10 4 s −1. The kinetic data have been compared with those obtained for the radical cations of 1-(4-methoxyphenyl)ethanol ( 2 ) and 1-(4-methoxyphenyl)-2,2-dimethyl-1-propanol ( 3 ), suggesting that the deprotonation rate increases when the C–H bond is forced into a conformation where it is almost aligned with the π-system. The conclusion that overlap between the scissile bond and the π-system is an important requisite for the occurrence of bond cleavage is also supported by the results of DFT calculations carried out for 1 + and 3 +.

Stereoelectronic effects in the reactivity of electrogenerated cation radicals of arylselenides

The role of stereoelectronic effects in the electrochemical oxidation of arylselenides Se-substituted by a trimethylsilylmethyl group and those with substituents bearing a carbonyl group have been considered. Although the HOMO of these compounds is formed of p z -type electrons of the ArSe moiety, the predominant contribution from the lone pair of Se makes the heteroatom more susceptible to direct electronic effects than to effects transmitted through the aromatic ring. The σ-p hyperconjugation and the interaction through space were shown to lower the charge localization on the reaction center and to stabilize cation radicals of these compounds, thus changing the control of the potential-determining reaction and promoting second order reactions.

Stereoelectronic effects in the side-chain bromination of alkylaromatic compounds

The role of stereoelectronic effects in the side-chain bromination of alkylaromatics has been assessed by a product study of the reactions of p-ethyltoluene, p-neopentyltoluene, 5,6-dimethylindane and 2,2,5,6-tetramethylindane with NBS in CCl 4